Project Summary/Abstract: Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus of global public health concern due to its ability to cause severe congenital abnormalities that include microcephaly, intrauterine growth restriction, fetal demise, and congenital eye (ocular) pathology. Ocular manifestations of ZIKV infection in congenitally infected humans include chorioretinal atrophy, optic nerve abnormalities, bilateral iris colobomas, intraretinal hemorrhages, and lens subluxation. The goal of this exploratory R21 proposal is to establish and characterize the pathogenesis of ocular ZIKV infection in adult and congenitally infected neonatal mice and to test our hypothesis that infectious ZIKV persists in the eye, which would have implications for chronic disease, recrudescence, and/or spread of ZIKV. Our preliminary findings suggest that ZIKV infects the eye and fails to be efficiently cleared. However, many important questions remain to be addressed. As an example, we do not know whether persistence of ZIKV RNA within the eye represents persistence of infectious virus or failure to clear viral RNA, which may still trigger chronic inflammation through engagement of pathogen recognition receptors. These proposed studies will enhance our understanding of ZIKV infection of the eye and will provide a foundation for studies to test potential therapies for ocular ZIKV disease in humans.